Statins are a class of compounds that competitively inhibit 3-hydroxy-3-methylglutaryl-co-enzyme A (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis (Igel et al. (2002) J. Clin. Pharmacol. 42:835). Statins lower blood lipid levels by reducing cholesterol biosynthesis in the liver. Accordingly, statins are known for their ability to help reduce levels of total cholesterol and low-density-lipoprotein cholesterol, which is of primary importance in preventing coronary heart disease. Id. Because of possible unwanted effects in non-liver tissues, systemic availability of statins is considered undesirable. Furthermore, to increase the level of HMG-CoA reductase inhibition, it is desirable to maximize hepatic bioavailability.
Certain statins possess properties that limit their hepatic bioavailability, thus decreasing their therapeutic effect and potentially increasing their systemic exposure. The inability to cross biological membranes by diffusion, for example, is one such property. Following ingestion, statins are absorbed through the intestine into the hepatic portal vein and distributed into the liver, which is the primary site of action and the primary site of cholesterol synthesis. Statin compounds that are hydrophilic, lipophobic, and/or have high molecular weights often show poor diffusive permeability across biological membranes in vivo. Accordingly, transport across biological membranes is only possible via a carrier-mediated transport mechanism that typically requires energy, often supplied by the hydrolysis of ATP.
One particular route of statin uptake involves absorption through the small intestine by a carrier-mediated transport mechanism, followed by absorption into hepatocytes, also via a carrier-mediated transport mechanism. Access to the site of action of drugs that are dependent on such carrier-mediated mechanisms depends to a large extent on the capacity of the transport mechanism across the membrane. In the intestine, if a statin is present in an amount that exceeds the capacity of the transport mechanism, the excess drug will be excreted. In the hepatic portal vein, if a statin is present in an amount that saturates the rate of transfer across the membrane, the excess is available for systemic exposure and non-hepatic tissue distribution, and can be detected in the blood.
Another property that can affect hepatic bioavailability is stability in an acidic environment. For example, certain of the statin compounds, such as pravastatin, are unstable in an acidic environment. Triscari et al. (1995) J. Clin. Pharmacol. 35:142. If administered by mouth, these statins can undergo non-enzymatic conversion in the stomach to relatively inactive metabolites. Id. To avoid this problem, a protective coating is typically used to delay the release of the statin until it has passed from the acidic environment of the stomach into the small intestine. For acid-stable statins, a protective coating is not required, but may be used as an additional control mechanism in a modified-release formulation. Thus, there is greater flexibility in achieving increased hepatic bioavailability through a modified-release formulation when acid-stable statins are used.
A further property that can limit the hepatic bioavailability of statins is water solubility. Some statin drugs are poorly water-soluble. Statins that are not soluble in water often have poor dissolution profiles, resulting in reduced bioavailbility when administered in vivo. The lack of good water-solubility properties of these drugs creates formulation difficulties that need to be addressed to improve their effectiveness.
A further property that can limit the hepatic bioavailability of certain statins is membrane diffusive permeability. A drug's difficulty in diffusing across biological membranes has a significant impact on drug absorption. Poor membrane permeability can be due to several factors, including the molecular size and charge of the molecule, as well as its hydrophobic/hydrophilic nature. For example, several statins exhibit poor or negligible membrane diffusive permeability due to their large molecular size, and thus rely effectively on being released at the sites of the carrier-mediated transport mechanisms to achieve absorption across biological membranes. In some instances, the limited membrane permeability results in variable or incomplete hepatic bioavailability. Further, even for poorly membrane-diffusive permeable statins that have acceptable oral bioavailability, the rate of absorption is slow and may affect the time to onset of action.
In addition, some statins show an acceptable rate and extent of absorption in the upper gastrointestinal tract, but only if the drug is released in the optimal region of the gastrointestinal tract. For this category of statins, while there may be a therapeutic benefit to altering the time course of drug absorption and systemic exposure after oral administration, the application of conventional controlled-release technology will not achieve the required extent of absorption because the natural site of absorption has been bypassed.
Thus, for statins that display one or more of these properties, which limit their hepatic bioavailability and may also increase their systemic exposure, there exists a need in the art for new formulations that allow for more optimal absorption in the intestine and in the liver. In particular, there is a need for acid stable, carrier-mediated transport statin formulations that provide release rates that maximize absorption in the intestine and in the liver. There also is a need for modified-release formulations that improve the hepatic bioavailibility of poorly water-soluble statins by improving their solubility, and that improve the hepatic bioavailability of large molecular weight statins by improving their permeability. Such modified-release formulations would help maximize statin absorption in the intestine and liver, and thus limit systemic exposure and the associated side effects.
Examples of specific carrier-mediated transport statins that display the properties of acid stability, poor water solubility, and large molecular weight discussed above include atorvastatin and rosuvastatin. Atorvastatin is a member of the statin drug class and is a fully synthetic pentasubstituted pyrrole that is stable in acidic environments. Because of its large molecular size (MW 1209 as the bis calcium salt; MW 557 as the free acid), atorvastatin shows poor membrane permeability, despite its lipophilic character. Atorvastatin is also poorly water-soluble, particularly in acidic environments. For example, as defined in the U.S. Pharmacopeia (2002), atorvastatin is considered “very slightly soluble.”
Atorvastatin calcium (sold as LIPITOR®) is thought to share the same mechanism in the liver as other statins through competitive inhibition of HMG-CoA reductase. Accordingly, atorvastatin is generally prescribed for reducing total cholesterol and low-density-lipoprotein cholesterol (LDL-C), which are primary targets in preventing coronary heart disease. Atorvastatin is particularly effective in reducing LDL-C levels (40-60% reduction) compared to other statins (25-35% reduction) (Malinowski (1998) Am J. Health-Syst Pharm 55:2253). In addition, atorvastatin appears to reduce levels of triglycerides more than other statins, although the mechanism has not been identified. Id. Atorvastatin is also more effective than other statins in reducing LDL-C in patients with homozygous familial hypercholesterolemia, a rare lipid disorder characterized by an inability to produce functional LDL receptors. Among other actions, atorvastatin also reduces the number of atherosclerotic lesions and reduces vascular smooth muscle cell proliferation. Malinowski (1998) Am. J. Health-Syst Pharm. 55:2253.
Unlike acid-unstable statins such as pravastatin, atorvastatin is stable in acidic environments like that found in the stomach. As with all carrier-mediated transport statins, once atorvastatin passes out of the stomach, it is absorbed in the intestine and then in the liver via carrier-mediated transport mechanisms. Only about 30% of orally administered atorvastatin is absorbed from the intestine. Similar to most other statins, atorvastatin undergoes extensive first-pass metabolism in the liver. About 70% or more of the atorvastatin absorbed from the intestine is taken up by the liver, resulting in a systemic bioavailability of the parent drug of approximately 12% and resulting in a systemic availability of active inhibitors (including the parent drug and its metabolites) of 30%. Id. Daily doses of more than 80 mg are not recommended. Peak plasma levels of atorvastatin are achieved 1 to 4 hours following ingestion, while steady-state plasma levels are attained in 32-72 hours. Id. When taken with food, the rate of absorption of atorvastatin is reduced (Cmax is reduced by 50% and tmax delayed by 10 hours), although the overall extent of absorption is only reduced slightly (area under the concentration curve (AUC) is reduced by only 12%). Id.
Several metabolites of atorvastatin appear to show HMG-CoA reductase inhibitory activity that is similar to that of the parent drug. These metabolites, which include o-hydroxylated and p-hydroxylated products, account for approximately 70% of atorvastatin's inhibitory activity. Atorvastatin and its metabolites, as with other statins, are excreted through the bile and are not recirculated through the liver or intestine. The half-life (t1/2) of atorvastatin in the plasma ranges from 13-24 hours, and has a mean value of 14 hours. Although the half-life of atorvastatin is less than 24 hours, it is normally administered only once per day since the duration of HMG-CoA reductase inhibition is approximately 20-30 hours due to the inhibitory activity of metabolites. This long-lasting inhibtion of atorvastatin may explain the observed increased reduction in lipid levels (Malinowski (1998) Am J. Health-Syst Pharm 55:2253).
Rosuvastatin is another new member of the statin family that is stable in acid and whose uptake is governed by carrier-mediated transport mechanisms. Rosuvastatin (which recently received FDA approval under the name CRESTOR®) is a fully synthetic single enantiomeric hydroxy acid, which belongs to a novel series of N-methanesulfonamide pyrimidine and N-methanesulfonyl pyrrole-substituted 3,5-dihydroxy-6-heptenoates (Cheng-Lai (2003) Heart Disease 5:72). Although rosuvastatin shares the common statin pharmacophore, it has an additional methane-sulfonamide group that increases its hydrophilicity. Because of its increased hydrophilic character and its large molecular size (MW 1001 as the bis calcium salt; MW 480 as the free acid) rosuvastatin has difficulty crossing biological membranes. Rosuvastatin is also relatively poorly soluble in water under both acidic and basic conditions. For example, as defined by the U.S. Pharmacopeia (2002), rosuvastatin is considered “sparingly soluble.”
As with other statins, rosuvastatin competitively inhibits HMG-CoA reductase and is thus useful in reducing levels of LDL-C, total cholesterol, and triglycerides, as well as increasing high-density-lipoprotein cholesterol (HDL-C) levels. Although rosuvastatin has only recently received final FDA approval, clinical studies suggest that it may be more effective in reducing LDL-C and total cholesterol levels than either pravastatin or simvastatin (Cheng-Lai (2003) Heart Disease 5:72). The extra methane sulfonamide group in rosuvastatin is believed to result in an additional ionic binding interaction with, and thus greater affinity for, HMG-CoA reductase. Accordingly, rosuvastatin has the lowest IC50 (0.16 nM in rat hepatocytes) and is the most potent inhibitor of sterol synthesis in hepatocytes of all the statins (White (2002) J. Clin. Pharmacol. 42:963).
Rosuvastatin reduces LDL-C levels by 34% to 65%, depending on the dosage. Rosuvastatin also increases HDL-C levels by 9% to 14% and reduces triglyceride levels by 10% to 35%. (Igel et al. (2002) J. Clin. Pharmacol. 42:835). Furthermore, rosuvastatin is well tolerated in humans at doses ranging from 1 to 40 mg, with Similar adverse side effects to those observed for pravastatin, atorvastatin, and simvastatin, such as rhabdomyolysis. Id. In particular, high doses of rosuvastatin (e.g., 80 mg and higher) have been associated with myopathy in phase III clinical trials. Id.
Rosuvastatin is metabolized slowly in the liver, where metabolism by cytochrome P450 isoenzymes is limited. Although one major N-desmethyl metabolite (formed primarily by CYP2C9 and CYP2C19) has been identified, it is seven-fold less active than the parent compound in inhibiting HMG-CoA reductase. Furthermore, it is believed that 90% of the inhibitory activity of rosuvastatin is due to the parent compound (White (2002) J. Clin. Pharmacol. 42:963). Accordingly, since rosuvastatin metabolism is slow and limited, clinically significant metabolically mediated interactions with other drugs are not likely (Cheng-Lai (2003) Heart Disease 5:72).
Rosuvastatin is selectively taken up into hepatocytes based on a carrier-mediated mechanism, with up to 90% of the absorbed dose extracted by the liver. (Igel et al. (2002) J. Clin. Pharmacol. 42:835). Although the presence of food decreases the rate of absorption, the overall extent of absorption remains constant. Peak plasma concentrations (Cmax), as well as the AUC, show a relatively linear relationship with respect to doses ranging from 5 to 80 mg, with a tmax that ranges from 3 to 5 hours. (Igel et al. (2002) J. Clin. Pharmacol. 42:835). Furthermore, rosuvastatin has a long elimination half-life (t1/2) of 20 hours. Clearance of rosuvastatin occurs mainly through biliary excretion (90%), while 10% is excreted in the urine (Cheng-Lai (2003) Heart Disease 5:72).
Unlike pravastatin (but like atorvastatin), rosuvastatin is stable in acidic environments like that found in the stomach. Once rosuvastatin passes out of the stomach, it is believed to enter the circulation via a carrier-mediated transport mechanism in the small intestine. Following absorption, rosuvastatin enters hepatocytes through a carrier-mediated transport mechanism. The organic anion transport polypeptide-C, which is expressed at high levels in hepatocytes, is thought to play a key role in selectively delivering rosuvastatin to the HMG-CoA reductase target enzyme in the liver (White (2002) J. Clin. Pharmacol. 42:963). Accordingly, the amount of rosuvastatin that is ultimately absorbed by the liver and available for binding to HMG-CoA reductase depends on the rates of uptake in the intestine and liver.